Immuno-Positron Emission Tomography with Zirconium-89-Labeled Monoclonal Antibodies in Oncology: What Can We Learn from Initial Clinical Trials?
Immuno-Positron Emission Tomography with Zirconium-89-Labeled Monoclonal Antibodies in Oncology: What Can We Learn from Initial Clinical Trials?
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DOI：
10.3389/fphar.2016.00131
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发表时间：
2016
影响因子：
5.6
通讯作者：
van Dongen GA
中科院分区：
文献类型：
--
作者：
Jauw YW;Menke-van der Houven van Oordt CW;Hoekstra OS;Hendrikse NH;Vugts DJ;Zijlstra JM;Huisman MC;van Dongen GA
选择合适患者的合适药物是一种有前途的方法，可以增加单克隆抗体（MAB）靶向治疗的临床益处。预期对MAB的体内生物分布和肿瘤靶向预测毒性和功效的评估有望指导个性化治疗和药物发育。使用锆-89（89ZR）标记的单克隆抗体的分子成像（PET），也称为89ZR-immuno-PET，可视化和量化放射性标记的mAb的摄取。该技术提供了一种潜在的成像生物标志物来评估目标表达以及mAb的肿瘤靶向。在这篇综述中，我们总结了最初的临床试验的结果，该试验的肿瘤学中是89ZR-rumuno-pet，并讨论了试验设计的技术方面。在具有89ZR-Immuno-PET的临床试验中，每个89ZR标记的MAB应满足两种要求，以实现其全部潜力。一个要求是，89ZR标记的MAB（成像剂量）的生物分布反映了治疗过程中药物的生物分布（治疗剂量）。另一个要求是，肿瘤在PET上的肿瘤摄取主要是由特异性，抗原介导的肿瘤靶向驱动的。初步试验通过在活检中显示了89zR标记的mAb的摄取和目标表达水平之间的相关性，从而有助于开发89zR-rimuno-pet作为成像生物标志物。这些结果表明89ZR-rumuno-pet反映了特定的抗原介导的结合。显示89ZR-rumuno-PET可以预测RIT的毒性，但迄今为止的结果表明，可以预测缺乏MABS或MAB-CREG-grug结合治疗的毒性。到目前为止，一项研究表明，与人类上皮生长因子-2（HER2） - 阳性乳腺癌的患者中，分子成像结合了早期反应评估能够预测用抗体 - 药物结合曲曲霉 - emtansine对治疗的反应。未来的研究将受益于标准化标准，以定义阳性肿瘤的吸收，可能通过定量分析支持，并通过将成像数据与相应的临床结果联系起来来验证。综上所述，这些结果鼓励进一步的研究开发89ZR-rumuno-pet，作为一种预测成像生物标志物，以指导个性化治疗以及潜在的药物开发中应用。
Selection of the right drug for the right patient is a promising approach to increase clinical benefit of targeted therapy with monoclonal antibodies (mAbs). Assessment of in vivo biodistribution and tumor targeting of mAbs to predict toxicity and efficacy is expected to guide individualized treatment and drug development. Molecular imaging with positron emission tomography (PET) using zirconium-89 (89Zr)-labeled monoclonal antibodies also known as 89Zr-immuno-PET, visualizes and quantifies uptake of radiolabeled mAbs. This technique provides a potential imaging biomarker to assess target expression, as well as tumor targeting of mAbs. In this review we summarize results from initial clinical trials with 89Zr-immuno-PET in oncology and discuss technical aspects of trial design. In clinical trials with 89Zr-immuno-PET two requirements should be met for each 89Zr-labeled mAb to realize its full potential. One requirement is that the biodistribution of the 89Zr-labeled mAb (imaging dose) reflects the biodistribution of the drug during treatment (therapeutic dose). Another requirement is that tumor uptake of 89Zr-mAb on PET is primarily driven by specific, antigen-mediated, tumor targeting. Initial trials have contributed toward the development of 89Zr-immuno-PET as an imaging biomarker by showing correlation between uptake of 89Zr-labeled mAbs on PET and target expression levels in biopsies. These results indicate that 89Zr-immuno-PET reflects specific, antigen-mediated binding. 89Zr-immuno-PET was shown to predict toxicity of RIT, but thus far results indicating that toxicity of mAbs or mAb-drug conjugate treatment can be predicted are lacking. So far, one study has shown that molecular imaging combined with early response assessment is able to predict response to treatment with the antibody-drug conjugate trastuzumab-emtansine, in patients with human epithelial growth factor-2 (HER2)-positive breast cancer. Future studies would benefit from a standardized criterion to define positive tumor uptake, possibly supported by quantitative analysis, and validated by linking imaging data with corresponding clinical outcome. Taken together, these results encourage further studies to develop 89Zr-immuno-PET as a predictive imaging biomarker to guide individualized treatment, as well as for potential application in drug development.